tbuckley/cabot-search huggingface dataset:
High quality colonoscopy: using textbook process as a composite quality measure
Authors: Karlijn J. Nass, Sascha C. van Doorn, Paul Fockens, Colin J. Rees, Maria Pellisé, Manon van der Vlugt, Evelien Dekker
Journal: Endoscopy (2023)

BACKGROUND : High quality colonoscopy is fundamental to good patient outcomes. "Textbook outcome" has proven to be a feasible multidimensional measure for quality assurance between surgical centers. In this study, we sought to establish the "textbook process" (TP) as a new composite measure for the optimal colonoscopy process and assessed how frequently TP was attained in clinical practice and the variation in TP between endoscopists. METHODS : To reach consensus on the definition of TP, international expert endoscopists completed a modified Delphi consensus process. The achievement of TP was then applied to clinical practice. Prospectively collected data in two endoscopy services were retrospectively evaluated. Data on colonoscopies performed for symptoms or surveillance between 1 January 2018 and 1 August 2021 were analyzed. RESULTS : The Delphi consensus process was completed by 20 of 27 invited experts (74.1 %). TP was defined as a colonoscopy fulfilling the following items: explicit colonoscopy indication; successful cecal intubation; adequate bowel preparation; adequate withdrawal time; acceptable patient comfort score; provision of post-polypectomy surveillance recommendations in line with guidelines; and the absence of the use of reversal agents, early adverse events, readmission, and mortality. In the two endoscopy services studied, TP was achieved in 5962/8227 colonoscopies (72.5 %). Of 48 endoscopists performing colonoscopy, attainment of TP varied significantly, ranging per endoscopist from 41.0 % to 89.1 %. CONCLUSION : This study proposes a new composite measure for colonoscopy, namely "textbook process." TP gives a comprehensive summary of performance and demonstrates significant variation between endoscopists, illustrating the potential benefit of TP as a measure in future quality assessment programs.
Air pollution and dementia
Authors: Andrew Sommerlad, Kathy Y Liu
Journal: BMJ (2023)

Due to the ageing global population, the number of people with dementia worldwide is predicted to rise from over 50 million in 2020 to more than 150 million by 2050, 1 with associated higher economic, social, and individual costs. 2 As such, identification of factors that can be targeted to reduce dementia's impact is urgently needed.The plausible effect of ambient air pollutants on brain pathology, via cerebrovascular disease or inflammation, 3 has contributed to an increasing volume of research exploring whether air pollution is a risk factor for dementia.In a linked BMJ paper, 4 Wilker and colleagues (doi:10.1136/bmj
Extinction of Lipomatous Hypertrophy of the Interatrial Septum FDG Uptake With Propranolol Premedication
Authors: Aurélien Callaud, Gilles Metrard, Hélène Besse, Matthieu Bailly, Frédérique Thibault
Journal: Clinical Nuclear Medicine (2023)

Lipomatous hypertrophy of the interatrial septum is a rare lesion of the heart. CT and cardiac MR are often sufficient to determine the benign lipomatous nature of the tumor and can avoid the need for histological confirmation. Lipomatous hypertrophy of the interatrial septum contains variable amounts of brown adipose tissue, resulting in different degrees of 18 F-FDG uptake in PET. We report the case of a patient with an interatrial lesion suspected of malignancy, discovered on CT and failing cardiac MR, with initial 18 F-FDG uptake. Final characterization was made thanks to 18 F-FDG PET with β-blocker premedication, avoiding an invasive procedure.
Design of medical tympanostomy conduits with selective fluid transport properties
Authors: Haritosh Patel, Ida Pavlichenko, Alison Grinthal, Cathy T. Zhang, Jack Alvarenga, Michael J. Kreder, James C. Weaver, Qin Ji, Christopher W. F. Ling, Joseph Choy, Zihan Li, Nicole L. Black, Paulo J. M. Bispo, Jennifer A. Lewis, Elliott D. Kozin, Joanna Aizenberg, Aaron K. Remenschneider
Journal: Science Translational Medicine (2023)

Implantable tubes, shunts, and other medical conduits are crucial for treating a wide range of conditions from ears and eyes to brain and liver but often impose serious risks of device infection, obstruction, migration, unreliable function, and tissue damage. Efforts to alleviate these complications remain at an impasse because of fundamentally conflicting design requirements: Millimeter-scale size is required to minimize invasiveness but exacerbates occlusion and malfunction. Here, we present a rational design strategy that reconciles these trade-offs in an implantable tube that is even smaller than the current standard of care. Using tympanostomy tubes (ear tubes) as an exemplary case, we developed an iterative screening algorithm and show how unique curved lumen geometries of the liquid-infused conduit can be designed to co-optimize drug delivery, effusion drainage, water resistance, and biocontamination/ingrowth prevention in a single subcapillary–length-scale device. Through extensive in vitro studies, we demonstrate that the engineered tubes enabled selective uni- and bidirectional fluid transport; nearly eliminated adhesion and growth of common pathogenic bacteria, blood, and cells; and prevented tissue ingrowth. The engineered tubes also enabled complete eardrum healing and hearing preservation and exhibited more efficient and rapid antibiotic delivery to the middle ear in healthy chinchillas compared with current tympanostomy tubes, without resulting in ototoxicity at up to 24 weeks. The design principle and optimization algorithm presented here may enable tubes to be customized for a wide range of patient needs.
Diverse rescue potencies of p53 mutations to ATO are predetermined by intrinsic mutational properties
Authors: Huaxin Song, Jiale Wu, Yigang Tang, Yuting Dai, Xinrong Xiang, Ya Li, Lili Wu, Jiaqi Wu, Ying Liang, Yangfei Xing, Ni Yan, Yuntong Li, Zhengyuan Wang, Shujun Xiao, Jiabing Li, Derun Zheng, Xinjie Chen, Hai Fang, Chenjing Ye, Yuting Ma, Yu Wu, Wen Wu, Junming Li, Sujiang Zhang, Min Lu
Journal: Science Translational Medicine (2023)

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor–suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations ( www.rescuep53.net ) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.
Selective Bcl-2 inhibition promotes hematopoietic chimerism and allograft tolerance without myelosuppression in nonhuman primates
Authors: Hajime Sasaki, Takayuki Hirose, Tetsu Oura, Ryo Otsuka, Ivy Rosales, David Ma, Grace Lassiter, Ahmad Karadagi, Toshihide Tomosugi, Abbas Dehnadi, Masatoshi Matsunami, Susan Raju Paul, Patrick M. Reeves, Isabel Hanekamp, Samuel Schwartz, Robert B. Colvin, Hang Lee, Thomas R. Spitzer, A. Benedict Cosimi, Pietro E. Cippà, Thomas Fehr, Tatsuo Kawai
Journal: Science Translational Medicine (2023)

Hematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene therapy, and transplant tolerance induction. However, severe myelosuppression and other toxicities after myeloablative conditioning regimens have hampered wider clinical use. To achieve donor hematopoietic stem cell (HSC) engraftment, it appears essential to establish niches for the donor HSCs by depleting the host HSCs. To date, this has been achievable only by nonselective treatments such as irradiation or chemotherapeutic drugs. An approach that is capable of more selectively depleting host HSCs is needed to widen the clinical application of HSCT. Here, we show in a clinically relevant nonhuman primate model that selective inhibition of B cell lymphoma 2 (Bcl-2) promoted hematopoietic chimerism and renal allograft tolerance after partial deletion of HSCs and effective peripheral lymphocyte deletion while preserving myeloid cells and regulatory T cells. Although Bcl-2 inhibition alone was insufficient to induce hematopoietic chimerism, the addition of a Bcl-2 inhibitor resulted in promotion of hematopoietic chimerism and renal allograft tolerance despite using only half of the dose of total body irradiation previously required. Selective inhibition of Bcl-2 is therefore a promising approach to induce hematopoietic chimerism without myelosuppression and has the potential to render HSCT more feasible for a variety of clinical indications.
Mechanosensing via a GpIIb/Src/14-3-3ζ axis critically regulates platelet migration in vascular inflammation
Authors: Rainer Kaiser, Afra Anjum, Lisa Maria Kammerer, Quentin Loew, Anastassia Akhalkatsi, Dario Rossaro, Raphael Escaig, Augustin Droste zu Senden, Ben Raude, Michael Lorenz, Christoph Gold, Kami Pekayvaz, Thomas Brocker, Jan Kranich, Julian Walter Holch, Karsten Spiekermann, Steffen Massberg, Florian Gaertner, Leo Nicolai
Journal: Blood (2023)

Platelets are first responders in thrombosis and hemostasis, but also central players in inflammation. Compared to platelets recruited to thrombi, immune-responsive platelets use distinct effector functions including Arp2/3-dependent migration along adhesive substrate gradients (haptotaxis), which prevents inflammatory bleeding and contributes to host defense. How platelet migration in this context is regulated on a cellular level is incompletely understood. Here, we use time-resolved morphodynamic profiling of individual platelets to show that migration, in contrast to clot retraction, requires anisotropic myosin IIa-activity at the platelet rear which is preceded by polarized actin polymerization at the front to initiate and maintain migration. Polarization of migrating platelets is coordinated by integrin GPIIb-dependent outside-in signaling via Gα13 to trigger tyrosine kinase c-Src/14-3-3ζ-dependent lamellipodium formation and functions independent of soluble agonists or chemotactic signals. Inhibitors of this signaling cascade, including the clinically employed ABL/c-Src inhibitor dasatinib, interfere predominantly with the migratory capacity of platelets, without major impairment of classical platelet functions. In murine inflammation models, this translates to reduced migration of platelets visualized by 4D intravital microscopy, resulting in increased inflammation-associated hemorrhage in acute lung injury. Finally, platelets isolated from dasatinib-treated leukemia patients prone to clinically relevant hemorrhage exhibit prominent migration defects, while other platelet functions are only partially affected. In summary, we define a distinct signaling pathway essential for migration, and provide novel mechanistic insights explaining dasatinib-related platelet dysfunction and bleeding.
Synchronous Squamous Cell Carcinoma of Rectum and Anal Canal Detected by FDG PET/CT—A Rare Entity
Authors: Shabana Abdul Jabbar, B. Selvakumar, Subhash Chandra Soni, Sameer Taywade, Poonam Elhence
Journal: Clinical Nuclear Medicine (2023)

Abstract Squamous cell carcinoma is the most common malignancy of the anal canal, and FDG PET/CT is recommended in its nodal staging, radiotherapy planning, and response assessment. We share an interesting case of dual primary malignancy of the anal canal and rectum, which was detected by 18 F-FDG PET/CT and confirmed on histopathology as synchronous squamous cell carcinoma.
The KMT2A recombinome of acute leukemias in 2023
Authors: C. Meyer, P. Larghero, B. Almeida Lopes, T. Burmeister, D. Gröger, R. Sutton, N. C. Venn, G. Cazzaniga, L. Corral Abascal, G. Tsaur, L. Fechina, M. Emerenciano, M. S. Pombo-de-Oliveira, T. Lund-Aho, T. Lundán, M. Montonen, V. Juvonen, J. Zuna, J. Trka, P. Ballerini, H. Lapillonne, V. H. J. Van der Velden, E. Sonneveld, E. Delabesse, R. R. C. de Matos, M. L. M. Silva, S. Bomken, K. Katsibardi, M. Keernik, N. Grardel, J. Mason, R. Price, J. Kim, C. Eckert, L. Lo Nigro, C. Bueno, P. Menendez, U. zur Stadt, P. Gameiro, L. Sedék, T. Szczepański, A. Bidet, V. Marcu, K. Shichrur, S. Izraeli, H. O. Madsen, B. W. Schäfer, S. Kubetzko, R. Kim, E. Clappier, H. Trautmann, M. Brüggemann, P. Archer, J. Hancock, J. Alten, A. Möricke, M. Stanulla, J. Lentes, A. K. Bergmann, S. Strehl, S. Köhrer, K. Nebral, M. N. Dworzak, O. A. Haas, C. Arfeuille, A. Caye-Eude, H. Cavé, R. Marschalek
Journal: Leukemia (2023)

Abstract Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A -partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’- KMT2A , two patients had a 5’- KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A , 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
T <sub>STEM</sub> -like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models
Authors: Deborah Meyran, Joe Jiang Zhu, Jeanne Butler, Daniela Tantalo, Sean MacDonald, Thu Ngoc Nguyen, Minyu Wang, Niko Thio, Criselle D’Souza, Vicky Mengfei Qin, Clare Slaney, Aaron Harrison, Kevin Sek, Pasquale Petrone, Kevin Thia, Lauren Giuffrida, Andrew M. Scott, Rachael L. Terry, Ben Tran, Jayesh Desai, H. Miles Prince, Simon J. Harrison, Paul A. Beavis, Michael H. Kershaw, Ben Solomon, Paul G. Ekert, Joseph A. Trapani, Phillip K. Darcy, Paul J. Neeson
Journal: Science Translational Medicine (2023)

Patients who receive chimeric antigen receptor (CAR)–T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8 + memory T cell progenitors that can become either functional stem-like T (T STEM ) cells or dysfunctional T progenitor exhausted (T PEX ) cells. To that end, we demonstrated that T STEM cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate T STEM -like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T STEM -like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4 + T cells during T STEM -like CAR-T cell production. Adoptive transfer of T STEM -like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of T STEM -like CAR-T cells and an increased memory T cell pool. Last, T STEM -like CAR-T cells and anti–programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8 + CAR + T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated T STEM -like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.
The secondary bile acid isoursodeoxycholate correlates with post-prandial lipemia, inflammation, and appetite and changes post-bariatric surgery
Authors: Panayiotis Louca, Abraham S. Meijnikman, Ana Nogal, Francesco Asnicar, Ilias Attaye, Amrita Vijay, Afroditi Kouraki, Alessia Visconti, Kari Wong, Sarah E. Berry, Emily R. Leeming, Olatz Mompeo, Francesca Tettamanzi, Andrei-Florin Baleanu, Mario Falchi, George Hadjigeorgiou, Jonathan Wolf, Yair I.Z. Acherman, Arnold W. Van de Laar, Victor E.A. Gerdes, Gregory A. Michelotti, Paul W. Franks, Nicola Segata, Massimo Mangino, Tim D. Spector, William J. Bulsiewicz, Max Nieuwdorp, Ana M. Valdes, Cristina Menni
Journal: Cell Reports Medicine (2023)

isoUDCA are determined by the gut microbiome d isoUDCA levels associate with higher post-prandial lipemia and fasting appetite d Higher isoUDCA levels correlate with worse liver function enzyme values d isoUDCA levels decrease post-bariatric surgery and after fiber supplementation
A Detailed Evaluation of the Effect of Prostate-specific Antigen–based Screening on Morbidity and Mortality of Prostate Cancer: 21-year Follow-up Results of the Rotterdam Section of the European Randomised Study of Screening for Prostate Cancer
Authors: Ivo I. de Vos, Annick Meertens, Renée Hogenhout, Sebastiaan Remmers, Monique J. Roobol
Journal: European Urology (2023)

Considering the long natural history of prostate cancer (PCa), long-term results of the European Randomised Study of Screening for PCa (ERSPC) are crucial.To provide an update on the effect of prostate-specific antigen (PSA)-based screening on PCa-specific mortality (PCSM), metastatic disease, and overdiagnosis in the Dutch arm of the ERSPC.Between 1993 and 2000, a total of 42376 men, aged 55-74 yr, were randomised to a screening or a control arm. The main analysis was performed with men aged 55-69 yr (n = 34831). Men in the screening arm were offered PSA-based screening with an interval of 4 yr.Intention-to-screen analyses with Poisson regression were used to calculate rate ratios (RRs) of PCSM and metastatic PCa.After a median follow-up of 21 yr, the RR of PCSM was 0.73 (95% confidence interval [CI]: 0.61-0.88) favouring screening. The numbers of men needed to invite (NNI) and needed to diagnose (NND) to prevent one PCa death were 246 and 14, respectively. For metastatic PCa, the RR was 0.67 (95% CI: 0.58-0.78) favouring screening. The NNI and NND to prevent one metastasis were 121 and 7, respectively. No statistical difference in PCSM (RR of 1.18 [95% CI: 0.87-1.62]) was observed in men aged ≥70 yr at the time of randomisation. In the screening arm, higher rates of PCSM and metastatic disease were observed in men who were screened only once and in a selected group of men above the screening age cut-off of 74 yr.The current analysis illustrates that with a follow-up of 21 yr, both absolute metastasis and mortality reduction continue to increase, resulting in a more favourable harm-benefit ratio than demonstrated previously. These data do not support starting screening at the age of 70-74 yr and show that repeated screening is essential.Prostate-specific antigen-based prostate cancer screening reduces metastasis and mortality. Longer follow-up shows fewer invitations and diagnoses needed to prevent one death, a positive note towards the issue of overdiagnosis.
PSMA PET/CT Detection of Chondromyxoid Fibroma
Authors: Albert Jang, Sydney A. Caputo, Madeline E. Hawkins, Joshua E. Talbert, Oliver Sartor
Journal: Clinical Nuclear Medicine (2023)

Abstract A 61-year-old man underwent a piflufolastat 18 F prostate-specific membrane antigen (PSMA) PET/CT scan due to a rising prostate-specific antigen level. The scan noted a focal cortical erosion on the CT scan in the right anterolateral tibia, and the PET showed an SUV max of 4.08. A biopsy of this lesion revealed a chondromyxoid fibroma. This rare case of a PSMA PET-positive chondromyxoid fibroma illustrates the importance of radiologists and oncologists not to assume an isolated bone lesion on a PSMA PET/CT scan as a bone metastasis from prostate cancer.
Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma
Authors: Robert J. Motzer, Thomas E. Hutson, Piotr Tomczak, M. Dror Michaelson, Ronald M. Bukowski, Stéphane Oudard, Sylvie Negrier, Cezary Szczylik, Roberto Pili, Georg A. Bjarnason, Xavier Garcia-del-Muro, Jeffrey A. Sosman, Ewa Solska, George Wilding, John A. Thompson, Sindy T. Kim, Isan Chen, Xin Huang, Robert A. Figlin
Journal: Journal of Clinical Oncology (2023)

Purpose A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-α) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Patients and Methods Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-α 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. Results Median overall survival was greater in the sunitinib group than in the IFN-α group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test ( P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-α group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor–signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-α ( P &lt; .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-α ( P &lt; .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). Conclusion Sunitinib demonstrates longer overall survival compared with IFN-α plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.
Global determination of reaction rates and lipid turnover kinetics in Mus musculus
Authors: Qishan Chen, Hu Li, He Tian, Sin Man Lam, Yilie Liao, Ziyin Zhang, Manyuan Dong, Shaoru Chen, Yuxiao Yao, Jiemiao Meng, Yong Zhang, Lemin Zheng, Zhuo-Xian Meng, Weiping Han, Guanghou Shui, Dahai Zhu, Suneng Fu
Journal: Cell Metabolism (2023)